chr7-92099831-A-G

Variant names:

• chr7-92099831-A-G
• rs142729919
• NM_005751.5:c.10858A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3 BP6_Very_Strong

The NM_005751.5(AKAP9):​c.10858A>G​(p.Ile3620Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000528 in 1,614,052 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I3620T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.399
• Publications: 5 publications found

Genes affected

AKAP9 (HGNC:379): (A-kinase anchoring protein 9) The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. Alternate splicing of this gene results in at least two isoforms that localize to the centrosome and the Golgi apparatus, and interact with numerous signaling proteins from multiple signal transduction pathways. These signaling proteins include type II protein kinase A, serine/threonine kinase protein kinase N, protein phosphatase 1, protein phosphatase 2a, protein kinase C-epsilon and phosphodiesterase 4D3. [provided by RefSeq, Aug 2008]

CYP51A1 (HGNC:2649): (cytochrome P450 family 51 subfamily A member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This endoplasmic reticulum protein participates in the synthesis of cholesterol by catalyzing the removal of the 14alpha-methyl group from lanosterol. Homologous genes are found in all three eukaryotic phyla, fungi, plants, and animals, suggesting that this is one of the oldest cytochrome P450 genes. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

CYP51A1 Gene-Disease associations (from GenCC):

• cataract

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 7-92099831-A-G is Benign according to our data. Variant chr7-92099831-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 191557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005751.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP9	NM_005751.5	MANE Select	c.10858A>G	p.Ile3620Val	missense	Exon 44 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.10834A>G	p.Ile3612Val	missense	Exon 44 of 50	NP_671714.1	Q99996-3
	AKAP9	NM_001379277.1		c.5503A>G	p.Ile1835Val	missense	Exon 23 of 29	NP_001366206.1	A0A2R8Y590

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP9	ENST00000356239.8	TSL:1 MANE Select	c.10858A>G	p.Ile3620Val	missense	Exon 44 of 50	ENSP00000348573.3	Q99996-2
	AKAP9	ENST00000491695.2	TSL:1	c.5503A>G	p.Ile1835Val	missense	Exon 23 of 29	ENSP00000494626.2	A0A2R8Y590
	AKAP9	ENST00000394534.7	TSL:1	c.3850A>G	p.Ile1284Val	missense	Exon 17 of 23	ENSP00000378042.3	H7BYL6

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 420 AN: 152138 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00980

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000744 AC: 187 AN: 251354 AF XY: 0.000552

Gnomad AFR exome AF: 0.00997

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000295 AC: 431 AN: 1461796 Hom.: 1 Cov.: 31 AF XY: 0.000249 AC XY: 181 AN XY: 727200

African (AFR) AF: 0.0105 AC: 351 AN: 33480

American (AMR) AF: 0.000559 AC: 25 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111944

Other (OTH) AF: 0.000712 AC: 43 AN: 60390

GnomAD4 genome AF: 0.00277 AC: 421 AN: 152256 Hom.: 1 Cov.: 32 AF XY: 0.00258 AC XY: 192 AN XY: 74454

African (AFR) AF: 0.00980 AC: 407 AN: 41544

American (AMR) AF: 0.000523 AC: 8 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00103 Hom.: 2

Bravo AF: 0.00294

ESP6500AA AF: 0.0113 AC: 50

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000931 AC: 113

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Long QT syndrome 11 (2)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Long QT syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
CADD	Uncertain	23
DANN	Benign	0.92
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.94	T
PhyloP100		0.40
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.054
Sift	Benign	0.28	T
Sift4G	Benign	0.47	T
Vest4		0.21
MVP		0.11
MPC		0.047
ClinPred		0.010	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.016
gMVP		0.074
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.77		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs142729919; hg19: chr7-91729145;